The proposed research seeks to identify and characterize newly expressed proteins (neo-antigens) that cause plasma cell reactions in medullary carcinomas (MC) of breast. It is our principal hypothesis that the marked infiltration of plasma cells and lymphoid elements reflects a local immune response against tumor that is responsible for the impression of a more favorable natural course of MIC tumors after surgery-only therapy. We will apply molecular cloning techniques to derive antibodies from tumor-infiltrating plasma cells, and then use these antibodies to retrieve the proteins whose new expression in the tumors caused the response. We prepared combinatorial phage Fab libraries from plasma cell-infiltrated MC tumors. We proved these tissues express highly focussed IgG antibody repertoires, supporting our premise of a specific immune reaction against a neo-antigen expressed in the tumor. Further, the dominant class-switched IgG isotype in the tumor and the high degree of CDR mutations suggest a T-dependent antigen, i.e., a protein. It was also shown that the neo-antigen is neither p53 nor Her2/neu, two dominant breast carcinoma-associated antigens, making it more likely (but not yet proving) that the neo-antigen is a previously undescribed protein or a protein not previously recognized to be tumor-associated. The neo-antigen could be a foreign (i.e., viral) protein or an aberrantly expressed or mutated normal protein that is present in the tumor. These important preliminary data justify the pursuit of the remaining effort to clone the eliciting antigen. Antigen will be cloned by screening of tumor-specific expression libraries with patient antibodies, while pursuing a parallel biochemical approach to ensure success in the cloning. The cloned and expressed neoantigen(s) is(are) then studied and assessed for possible roles in the malignant proliferation.